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Infectious Disorders - Drug Targets, 2021, 21, 000-000 1
RESEARCH ARTICLE
1871-5265/21 $65.00+.00 © 2021 Bentham Science Publishers
Increased Level of Interleukin-8 in Female Genital Tract After HP
Eradication Lines
Viacheslav Kravtsov1*, Tatiana Surovtceva2, Maria Taame3, Yuri Grukhin2 and Natalia Kalinina4
1S.M. Kirov Military Medical Academy, Saint-Petersburg, Russian Federation; 2Saint-Petersburg State public health
Institution “City Clinical Hospital” №.20, Saint-Petersburg, Russian Federation; 3Institute of Public Health and Clini-
cal Nutrition, University of Eastern Finland (UEF), Kuopio, Finland; 4Nikiforov Russian Centre of Emergency and
Radiation Medicine, EMERCOM, Saint-Petersburg, Russian Federation
!
A R T I C L E H I S T O R Y!
Received: July 09, 2020
Revised: September 28, 2020
Accepted: October 20, 2020
DOI:
10.2174/1871526520666210104091545!
Abstract: The study investigated the levels of cytokines IL-8 and TNF-α in vaginal secretion in a
group of female patients with Helicobacter-associated acid-related diseases who were or were not
treated with anti- Helicobater pylori treatment (AHT). It turned out that the secretory cytokine
(chemokine) IL-8 is dramatically increased in the vaginal mucosa in patients treated with antibiotics,
specifically in post-menopause women. Thus, we conclude that helicobacter pylori eradication treat-
ment affects the immune status of the female genital tract.!
Keywords: Local immunity, female genital tract, interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α), Helicobacter Py-
lori associated acid-related diseases, AHT, eradication lines.
1. INTRODUCTION
The widespread use of antibiotics in treating infectious
diseases caused by pathogenic bacteria is often accompanied
by the occurrence of mucosal dysbiosis. It is considered that
the cause of dysbiosis after taking antibiotics is related to
their bactericidal effect not only on pathogenic bacteria but
also on normal microflora. As a result, immunological and
metabolic shifts occur after antibiotic treatment in the mu-
cous membranes along with quantitative and qualitative
changes in obligate microflora and changes of habitation
environment [1-4]. Experimental models (linear animals)
were used in order to study the effect of antibiotics on im-
munity [5, 6], and experimental tests in vitro were carried
out [8, 7]. The effect of a short course of amoxicillin or er-
tapenem on the immunity of healthy pigs was conducted [3].
Additionally, amoxicillin was studied in clinically healthy
people in a group of volunteers [9]. In clinical studies, we
can get adequate and informative learning about immunity
parameters in patients with acid-related diseases (ARD)
after completing courses of Helicobacter pylori eradication
therapy. That includes two antibiotics, and two therapy lines
that are conducted if necessary, and sometimes even three
therapy lines of eradication [10-14].
It is known that antibiotic therapy can affect the func-
tional capacity of cells of the immune system as well as the
regulation of the immune response, both at local and sys-
temic levels. According to some authors` opinion, the direct
*Address correspondence to this author at the S.M. Kirov Military Medical
Academy, Saint-Petersbu rg, Russian Federation; Tel: +79602571546;
E-mail: kvyspb@mail.ru
suppressive effect of antibiotics on effector cells of the im-
mune system should be one of the pathogenetic mechanisms
of the onset of candidiasis after antibiotic therapy [15, 16].
Anti-helicobacter pylori treatment (AHT), in our opin-
ion, is a suitable model for studying the effect of antibiotics
on the immune status in patients for the following reasons.
Firstly, the AHT is carried out as standard in the schemes
strictly regulated by th e Maastricht agreements [12, 17].
Secondly, these agreements also regulate the second and
third lines of the AHT (in case of inefficiency of the first
line of treatment); thus, the doses of antibiotics used on the
second course of AHT become essential to study their ef-
fects after treating [17]. Thirdly, all patients in the same
mode of time have taken the same antibiotics with the same
dosages, i.e., standard study conditions are met. Fourthly,
patients with HP-associated Acid-Related Diseases (ARD),
as a rule, do not have acute inflammatory processes (chronic
gastritis is most common), which is very important for an
adequate assessment of changes in the parameters of sys-
temic and local immunity. Practical importance is present by
studying mucous membranes of the female genital tract
(FGT) after taking antibiotics since they are often accompa-
nied by dysbiosis, in particular, vulvovaginal candidiasis
(VVC) [18, 19]. In connection with all the above, the pur-
pose of our work was to identify distortions of local immu-
nity parameters in the vaginal mucosa in women with HP-
associated ARD who have taken two courses of AHT for
this purpose. We have determined the parameters of local
immunity (cytokines IL-8 and TNF-α) in the vagin al secre-
tion in patients who took AHT and in the comparison group
of patients with ARD who did not take antibiotics.
2 Infectious Disorders - Drug Targets, 2021, Vol. 21, No. 00 Kravtsov et al.
The objective of the study was to identify distortions of
local immunity par ameter s in the vaginal mucosa in women
with HP-associated ARD who have taken two courses of
anti-helicobacter pylori treatment (AHT).
2. MATERIALS AND METHODS
The present study used general scientific methods of a
comparative prospective analysis.
2.1. The Examined and Comparison Groups
The sample of patients included in the study was se-
lected as a result of their purposeful selection at the City
Clinical Hospital No. 20 and the Federal State Budgetary
Institution " Nikiforov Russian Centre of Emergency and
Radiation Medicine" of the EMERCOM of Russia in the
period from 2006 to 2011. A total of 337 women were ex-
amined, aged 28 to 67 years.
Initially, the study was conducted among women with
HP-associated ARD (K28 with chronic gastritis and К.29
according to ICD 10) and duodenal ulcer (K27 - according
to ICD 10). All patients were positive for Helicobacter py-
lori infection of the gastric mucosa as a result of fibrogastro-
endoscopic with gastrobiopsies (gastric biopsy specimen),
which were examined by the urease and bacterioscopic test
method. Additionally, the selection of patients was made on
the following clinical criteria: the presence of symptoms of
functional dyspepsia with recurrent epigastric pain, a burn-
ing sensation in the epigastrium, a feeling of overflow in the
epigastric region after eating with early saturation, which
were noted for at least the last 6 months. The examination of
patients was done with their informed consent in compli-
ance with ethical standards.
2.2. Study Groups
2.2.1. Anti-Helicobacter Antibiotic Treatment
Eradication of HP was achieved in 86 women of repro-
ductive age after the first line of AHT, prescribed by a gas-
troenterologist. The first line included taking proton pump
inhibitor drugs (pariet) and two an tibiotics (klacid and
amoxicillin) for 10 days. Controlling eradication was carried
out in different patients by different methods, mainly by
urease and bacterioscopic methods of gastrobiopaths (gas-
tric biopsy specimen). Thirty-one out of 117 patients agreed
to undergo the second course of AHT after the ineffective
first course of AHT(i.e., H. pylori eradication was not
achieved).
2.2.2. Inclusion/ Exclusion Criteria
The criteria for patient inclusion into study groups were
the absence of signs of inflammation in the female genital
tract (according to the results of the PAP test and determina-
tion of the biocenosis in the lateral vaginal fornix) and ab-
sence of sexually transmitted infections (STDs).
Our study groups (Group 1 and Group 2) included
women who did not achieve HP eradication after the first
line eradication of H. pylori treatment. After 1-2 months, the
second line of anti-Helicobacter therapy (AHT) was carried
out in case of ineffectiveness of the first line of AHT ac-
cording to the following scheme: PPI (Proton Pump Inhibi-
tor), Pariet, tetracycline (500 mg 4 times a day), metronida-
zole (500 mg 3 times a day), and bismuth tripotassium di-
citrate (240 mg 2 times per day) lasting 14 days. Study
group 1 consisted of 9 women of reproductive age, whose
PAP test revealed cytograms within the normal range (ac-
cording to Bethesda) and who had no signs of inflammation,
according to cytological examination. Study group 2 in-
cluded 21 women (55-67 years) in postmenopausal stage
with an atrophic type of cytological smear according to the
PAP test.
Women of the study groups agreed to be voluntarily
examined by a gynecologist after taking medication for 7-14
days before the start of the second line of anti-Helicobacter
therapy. Women of study groups came to an appointment
with a gynecologist in a planned manner while being admit-
ted to the General Hospital №20 in Saint-Petersburg. The
patients visited the gynecologist's office, where they had a
standard procedure in taking vaginal secretions for immu-
nological studies in the next 7-14 days after completion of
the second line of anti-helicobacter therapy.
The comparison group at the beginning consisted of 220
women of reproductive age without gastrointestinal pathol-
ogy who had not received antibiotic therapy in the last 6
months and underwent routine preventive examinations by a
gynecologist. Our comparison study groups of the final
study (Group 3 and Group 4) included women with no HP-
associated ARD and were not given anti-helicobacter treat-
ment. Group 3 consisted of 11 women of reproductive age
(28-45 years) whose smear cytograms corresponded to nor-
mal (according to Bethesda). Group 4 consisted of 13
women (56-67 years old) in the post-menopausal period
who had an atrophic smear type (in PAP test) according to a
cytological examination. We excluded patients with diabetes
mellitus, as well as women who recently (no more than 6
months ago) visited the gynecologist and were assigned
intravaginal hygienic and medical manipulations with the
use of antiseptics.
2.2.3. Cytological Studies (PAP-test)
Cytological smears obtained with a cytobrush were
stained standardly with hematoxylin-eosin. Microscopic
examination was performed at magnifications of 400 × and
1000 ×. The degree of inflammation in the vagina was as-
sessed in smears obtained from the lateral vaginal fornix,
also stained with hematoxylin-eosin, in terms of a ratio of
polymorphonuclear leukocytes to vaginal epithelial cells.
Patients with atrophic colpitis (postmenopausal) and pa-
tients of reproductive age with inflammatory smear type
were excluded from immunological studies. The study
groups included only those women whose ratios of poly-
morphonuclear leukocytes to vaginal epithelium cells were
less than 1:1, and there was no bacterial vaginosis.
2.2.4. Immunological Research Examination
Determination of cytokines IL-8 and TNF-α was done
from vaginal secretion, which was obtained while visiting a
gynecologist. Study materials from women of reproductive
age were taken in the middle of the menstrual cycle (on the
10-17th day). The number of IL-8, TNF-α w as determined
by enzyme immunoassay (EIA) on a plate with the corre-
Increased Level of Interleukin-8 in Female Genital Tract Infectious Disorders - Drug Targets, 2021, Vol. 21, No. 00 3
sponding monoclonal antibodies, using sets of companies
LLC «Cytokine» and Protein Contour, respectively. The
number of detected antigens were expressed in pg/ml.
3. RESULTS AND DISCUSSION
We conducted our studies separately in two age groups
as the state of the mucous membrane of the g enital tract in
women depends on their endocrine profile and atrophic
changes that occur in the vaginal and cervical epithelium
with age; group 1 and its corresponding comparison group 3
included women in reproductive age, and group 2 with its
comparison group 4 included women in the postmenopausal
period. We emphasize that we did not include cases where
signs of inflammation were found in cytological smears or
infection.
Fig. (1a, b) shows the distribution of patients of repro-
ductive age with ARD, who passed two lines of AHT
(Group 1), and patients who did not pass the eradication
course (comparison group - group 3) in terms of " IL-8 con-
tent in the vaginal secretion".
There is a greater range of variability in IL-8 indicator in
the group after AHT (Fig. 1a) than in the comparison group.
The content of IL-8 in group 3 in the vaginal secretion ex-
ceeded 40 pg/ml only in one case. On the contrary, more
than half of the patients had values above 40 pg/ml (and
even one patient had exceeded 550 pg/ml) in the groups
after AHT, which influenced the formation of a high mid-
range value. The average value of “IL-8 content in vaginal
secretion” in the group of reproductive age women after
AHT was 121.6 pg/ml and was 26.3 pg/ml in the corre-
sponding comparison group. Nevertheless, despite such a
significant trend of differences in the average value, no sig-
nificant differences between these two groups were found
by Mann-Whitney U-test (p> 0.05).
Similar distributions of patients after AHT in the post-
menopausal period (Group 2) and the corresponding com-
parison group (Group 4) are shown in Fig. (1b). It is obvi-
ous that the distribution pattern of patients from the com-
parison group of post-menopausal women turned out to be
the same as in the comparison group of reproductive-age
women. All patients (with the exception of one) had IL-8
values not exceeding 50 pg/ml. On the contrary, exactly
two-thirds of women showed IL-8 above 100 pg/ml in vagi-
nal secretions after taking AHT. Note that the groups of
postmenopausal women were much more numerous than the
groups of women of reproductive age considered above and
this, among other things, allowed us to reveal significant
differences. It turned out that the differences in the content
of IL-8 in the vaginal secretion between postmenopausal
women who took and did not take antibiotics were even
more obvious of almost eightfold. Increased IL is not ob-
served and remained within normal limits in six out of
twenty-one patients (28%). The average value of IL-8 in the
vaginal secretions in the treated group was 346 pg/ml, and
in the comp arison group who did not take antibiotics was 41
pg/ml. The Mann-Whitney U-test revealed significant dif-
ferences (p <0.05).
Thus, the data presented above indicated the effect of
AHT on the level of pro-inflammatory cytokine
Fig. (1). Distribution of patients with Helicobacter-associated ARD in terms of "IL-8 content in the vaginal secretion" in women of reproduc-
tive age (a), and postmenopausal women (b) (Unfilled symbols - IL8 in patients after treatment of H. pylori, painted symbols - IL8 in pa-
tients who were not taking antibiotics; ER- IL8 in women of reproductive age with AHT; EP- IL8 in postmenopausal women with AHT; CR-
IL8 in the control group of reproductive age without AHT; CP -IL8 in the control group of postmenopausal without AHT). (A higher resolu-
tion / colour version of this figure is available in the electronic copy of the article).
4 Infectious Disorders - Drug Targets, 2021, Vol. 21, No. 00 Kravtsov et al.
(chemokine) IL-8 in vaginal secretion. The level of IL-8 in
the vaginal secretion increased significantly after the second
line of AHT in women in the postmenopausal period, re-
vealing the reliability of this fact.
Now let’s consider how much the content of another
pro-inflammatory cytokine, TNF-α, has changed in vaginal
secretion. Group 1 had a slightly larger range of variation of
the characteristic “TNF-content in the vaginal secretion”
with a range of variability from 2.0 pg/ml to 201 pg/ml and
an arithmetic mean of 57.4 pg/ml. The average was 39.9
pg/ml in the comparison group (Group 3), with a variability
range from 10 pg/ml to 95 pg/ml. The Mann-Whitney U-test
between these two samples did not reveal significant differ-
ences similar to the case of IL-8 (p> 0.05). There were also
no significant differences in the “TNF-α average in vaginal
secretion” in post-menopausal women (Fig. 1b) (p> 0.05,
according to the Mann-Whitney U-test), although the mean
values showed an increase of TNF- α in women after AHT.
The mean average in the vaginal secretion of TNF-α in
those treated groups was 46.2 pg/ml, and 29.1 pg/ml in
those who were not treated. These definitions of an average
of TNF-α in the vaginal secretion in patien ts with ARD in-
dicate that there are no significant differences in this indica-
tor between groups of patients who have taken and those
who have not taken AHT courses.
Attention is drawn to the fact that the range of variation
in the content of cytokines in the vaginal secretion was al-
ways greater in the groups of women who took antibiotics
through their prescribed AHT. We also noted that w e did
not observe patients in comparison groups with indicators
“IL-8 content in the vaginal secretion” and “TNF-α content
in the vaginal secretion”, wh ich would be higher than nor-
mal (If you consider 0-50 for IL-8 and 0-70 for TNF-α). In
contrast, abnormalities in the direction of increasing IL-8
content in vaginal secretions (and sometimes very sharp)
were observed in 4 out of 9 women of reproductive age and
in 15 out of 21 postmenopausal women in groups of women
who took AHT. It can be concluded that the indicator “IL-8
content in the vaginal secretion” in postmenopausal women
responds more strongly towards a significant increase in
response to AHT. In a study performed on healthy adult
men who voluntarily took amoxicillin for 5 days (125 mg
twice a day), no abnormalities were observed in the content
of TNF-α in mucous membranes of the gastrointestinal tract
after taking the antibiotic [9]. The same results concerning
the female gen ital tract were obtained and presented in this
work by us. Immunity in the mucous membrane of the fe-
male genital tract (FGT) depends on the influence of immu-
noglobulins, cytokines, antimicrobial peptides, and repro-
ductive hormones. Proinflammatory cytokines, including
chemokine IL-8, as well as anti-inflammatory cytokines, can
be produced by epithelial cells of FGT themselves. This fact
is established in the data of immunohistochemical studies
[20, 21, 22, 23] and even by electron microscopy [24]. The
mechanism of the cytokine link of immune defense in the
mucous membrane of FGT is triggered after microbial
agents bind to pattern recognition receptors (PRRs) and toll-
like receptors (TLRs), which are expressed and present in
the epithelial cells of FGT [25, 26].
Consequently, these receptors are considered as a signal-
ling pathway for the induction of epithelial cell production
of pro-inflammatory cytokines in FGT [20, 27, 28]. A sig-
nificant increase in the level of cytokine-chemokine IL-8
(but not cytokines IL-1 beta and IL-6) in cervicovaginal
swabs is found in bacterial vaginosis [29, 30, 31, 32] and
cervicitis [ 32, 33]. At the same time, the production of IL-8
chemoattractant by epithelial cells of FGT can also be car-
ried out in the absence of infection, while the main migra-
tion of neutrophils caused by chemoattraction of FGT
epithelial cells results from the synerg istic effect of IL-8 and
GM-CSF (granulocyte colony-stimulating factor), which is
also produced by epithelial cells of FGT [34, 35]. We
should not detract from the value in the immune protection
of FGT by immunocompetent cells. Cytokines produce
mononuclear cells located in FGT [36, 37]. It has been
noted that in our research, we included only those women
who did not have signs of inflammation in FGT (with ratios
of polymorphonuclear leukocytes to vaginal epithelial cells
less than 1:1 in the lateral vaginal fornix and absence of
bacterial vaginosis). Therefore, we assume in this study that
the main pool of cytokines is produced by epithelial cells,
and not by immunocompetent mononuclear cells and poly-
morphonuclear leukocytes, which have come to the inflam-
mation site.
Therefore, it remains to answer the question, what could
serve as a stimulus for the production of cytokine
(chemokine IL8) by epithelial cells of FGT after taking an-
tibiotics? Apparently, such stimulation occurred through the
pattern (toll receptors), and microbial agents from the rec-
tum appeared as a stimulating factor. It can be assumed that
these were mainly HP antigens (as part of the cell wall of
bacterial HP cells degenerated under the influence of antibi-
otics) [38], which are known to have very high immuno-
genicity and affinity for TLRs [39].
CONCLUSION
Summarizing all the results of the study about the effect
of AHT on the levels of IL-8 and TNF-α in vaginal secre-
tion, we found out non-target effect on th e secretory cyto-
kine (chemokine) IL-8 in the vaginal mucosa after the sec-
ond line of HP eradication, in particular, in post-menopausal
women. Additional studies should be done to investigate the
influence of AHT on the female genital tract.
LIST OF ABBR EVIATIONS
IL-8 = Interleukin-8
TNF-α = Tumor necrosis factor-alpha
ARD = HP-associated Acid- related Diseases
AHT = Anti-helicobacter pylori treatment
FGT = Female genital tract
VVC = Vulvovaginal candidiasis
PRRs = Pattern recognition receptors
TLRs = Toll-like receptors
GM-CSF = granulocyte colony-stimulating factor
Increased Level of Interleukin-8 in Female Genital Tract Infectious Disorders - Drug Targets, 2021, Vol. 21, No. 00 5
ETHICS APPROVAL AND CONSENT TO
PARTICIPATE
All studies were carried out with the voluntary consent
agreement of patients and healthy persons who underwent
routine medical examinations at the Nikiforov Russian Cen-
tre of Emerg ency and Radiation Medicine, EMERCOM of
Russia. The study was approved by the ethics committee of
the Nikiforov Russian Centre of Emergency and Radiation
Medicine, EMERCOM.
HUMAN AND ANIMAL RIGHTS
The reported experiments on human subjects were per-
formed in accordance with the ethical standards of the
committee responsible for human experimentation (institu-
tional and national) and with the Helsinki declaration of
1975, as revised in 2013
(http://ethics.iit.edu/ecodes/node/3931).
CONSENT FOR PUBLICATION
Not applicable.
AVAILABILITY OF DATA AND MATERIALS
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
The authors are grateful to professor Natalia Ibragimova,
Natalia Davydova, and Ludmila Chynenova for their assis-
tance in conducting cytology and immunology assays.
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